Many types of anticancer agents are currently in clinical use. These clinically applied anticancer agents encounter many problems, such as the emergence of cancer cells that have acquired resistance to once-effective anticancer agents, lowering their efficacy toward solid cancers. The efficacy of anticancer agents against solid tumors is thought to decrease as the inner part of a solid tumor becomes hypoxic when it reaches a certain size or larger.
In progressive cancers, the inner cancer cells proliferate faster than surrounding cells. The supply of new blood vessels to these inner cells thus becomes inadequate, blood supply becomes insufficient, and hypoxic conditions result. For example, in Teicher, B. A. “Hypoxia and drug resistance.” Cancer Metastasis Rev., 13:139-168, 1994; Brown, J. M. & Giaccia, A. J. “The unique physiology of solid tumors: opportunities (and problems) for cancer therapy.” Cancer Res., 58:1408-1416, 1998; Brown, J. M. “Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies.” Mol. Med. Today, 6:157-162, 2000; Luk, C. K., Veinot-Drebot, L., Tjan, E. & Tannock, I. F. “Effect of transient hypoxia on sensitivity to doxorubicin in human and murine cell lines.” J. Natl. Cancer Inst., 82:684-692, 1990; Sakata, K., Kwok, T. T., Murphy, B. J., Laderoute, K. R., Gordon, G. R., Sutherland, R. M. “Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance.” Br. J. Cancer, 64:809-814, 1991; Sanna, K. & Rofstad, E. K. “Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro.” Int. J. Cancer, 58:258-262, 1994, it is disclosed that cancer cells in apoxic conditions are more resistant to chemotherapy and radiation therapy than cancer cells under high-oxygen conditions, and that apoxic conditions induce drug resistance in solid cancer cells. The results described in the above-mentioned literature show that apoxic conditions induce anti-apoptosis factors in solid cancer cells.
Pim-1 is a serine/threonine kinase initially identified in T cell lymphomas caused by murine leukemia virus (MuLV) as a gene frequently activated by leukemia virus insertion (Cuypers, H. T., Selten, G., Quint, W., Zijlstra, M., Maandag, E. R., Boelens, W., van Wezenbeek, P., Melief, C., Berns, A. “Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region.” Cell, 37:141-150, 1984; and Selten, G., Cuypers, H. T. & Berns, A. “Proviral activation of the putative oncogene Pim-1 in MuLV induced T-cell lymphomas.” EMBO J, 4:1793-1798, 1985. Further, Pim-1 in the cytoplasm has been reported to function as a factor for inhibiting apoptosis in various hematopoietic cells (Pircher, T. J., et al. “Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death.” Oncogene, 19:3684-3692, 2000; and Lilly, M. & Kraft, A. “Enforced expression of the Mr 33,000 Pim-1 kinase enhances factor-independent survival and inhibits apoptosis in murine myeloid cells.” Cancer Res., 57:5348 5355, 1997. Therefore, substances that can inactivate Pim-1 would be effective for preventing/treating solid cancers, and various Pim-1-induced disorders.
Therefore, an objective of the present invention is to provide methods of screening for novel compounds that exhibit anticancer activity. Another objective of the present invention is to provide methods of screening for preventive and therapeutic agents for cancer, in which the agents prevent and treat cancer by inactivating Pim-1.